Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP

Elevated expression of the activating Fc gamma receptor (Fc gamma R) I and Fc gamma RIIa together with decreased expression of the inhibitory Fc gamma RIIb are involved in the pathogenesis of primary immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) have been used clinically for the management of ITP; however, little is known about the effect of TPO-RAs on Fc gamma R modulation in ITP. In this prospective study, we measured the alteration in monocyte Fc gamma R expression from 21 corticosteroid-resistant/relapsed patients with chronic ITP receiving eltrombopag therapy. Results showed that the mRNA and protein levels of Fc gamma RIIb were significantly elevated after 6-week eltrombopag treatment. Concurrently, Fc gamma RI and IIa levels decreased remarkably, whereas Fc gamma RIII expression did not change. In vitro phagocytosis assays indicated that a shift in the balance of Fc gamma R toward inhibitory Fc gamma RIIb on monocytes was accompanied with a considerable decrease in monocyte/macrophage phagocytic capacity. The response to eltrombopag therapy in patients with ITP was associated with Fc gamma R phenotype and functional changes of monocytes/macrophages. Moreover, the plasma transforming growth factor-beta 1 (TGF-beta 1) concentrations increased significantly in eltrombopag responders. Modulation of monocyte Fc gamma R balance by TPO-RAs was also found in a murine model of ITP established by transferring splenocytes from immunized CD61 knockout mice into CD61(+) severe combined immunodeficient mice. Romiplostim administration in ITP mice significantly upregulated inhibitory Fc gamma RII expression and downregulated activating Fc gamma RI expression. These findings showed that recovery of platelet counts after TPO-RA treatment in ITP is associated with the restoration of Fc gamma R balance toward the inhibitory Fc gamma RIIb on monocytes, and suggested that thrombopoietic agents have a profound effect on immune modulation in ITP. This study is registered at ClinicalTrials.gov as #NCT01864512. (Blood. 2016;128(6):852-861)